Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that establishes life-long latent infections in sensory ganglia. During severe HSV-1 infections, usually in immunocompromised hosts or neonates, the virus can cause life-threatening encephalitis or blindness resulting from ocular lesions. Infection of neurons occurs through fusion of the HSV-1 envelope and a neuronal membrane. It has been determined that four HSV-1 glycoproteins, gB, gD, and the heterodimer gH-gL, are essential for fusion. In an attempt to study membrane fusion in neurons, we have developed a model where non-neuronal cells expressing the essential viral fusion glycoproteins and a reporter gene mediate fusion with neurons. We propose to use this model to study the specific requirements for neuronal membrane fusion. In addition, we will use neurons cultured from knock-out mice of known HSV-1 entry receptors (HVEM and nectin-1) as well as panels of gB, gD, gH, and gL mutants to ascertain the determinants of fusion in our system. In the end, understanding the mechanism of viral glycoprotein-induced membrane fusion in neurons can lead to potential targets for antiviral drugs that block neuronal infections at the virus entry stage.